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ARTICLE IN BRIEF

Dr. Mark F. Mehler describes the unconventional paths and methods that led him to study and unravel the biology behind gene-environment interactions.

Growing up in Manhattan, the last thing Mark Mehler, MD, the son of first-generation European immigrants, was interested in was medicine. “I was fascinated with everything from astrophysics to poetry, but I couldn't see one particular field of study being capable of making me feel fulfilled for the rest of my life,” recalled Dr. Mehler, now the chair of neurology at Albert Einstein College of Medicine, who presented the Presidential Lecture at the 2012 AAN annual meeting in New Orleans.

Dr. Mehler confesses that he is, in many ways, an atypical neurologist — and department chair. For one thing, he said, “Most people who go into medicine know that they want to do that from the time they're kids. I didn't. In fact, I didn't really think about what I wanted to do when I grew up.”

That's another way Dr. Mehler differs from the average physician. “I'm not a planner. I was very lucky. I went all through the New York City public schools, a great experimental elementary school in Harlem and Stuyvesant High School, one of the best science high schools in the country. And then I just thought, ‘Oh, Columbia’s convenient. I'll go there.'”

After majoring in psychology and comparative literature at Columbia, Dr. Mehler was nearing the end of his college career and hadn't settled on what to do next. And then he hit on medicine. “It encompassed all of the disciplines that appealed to me: it would allow me to conduct research, which I liked, and to be involved in global health, governmental health policy work — all those things.”

When Dr. Mehler told his parents of his decision to apply to medical school, their reaction, too, was atypical. “My father was horrified. He said, ‘Why don’t you go to Malibu and become a surfer, you'll have a happier life?'” Dr. Mehler's parents had raised him to love knowledge and love learning, to eschew ambition and ego — something they probably imagined he would acquire in excess while becoming a physician.

But as it turned out, he has retained that lack of ego and personal ambition throughout his career, and it's something he believes has served him well as a department chair at Einstein — the school he attended for his undergraduate medical education and fell so in love with that he has remained there for his entire medical career.

“The second I decided on medicine I knew that I wanted to pursue neurology and basic research. I had always been interested in the brain and cognition, in math and science,” Dr. Mehler said. He had also been exposed to neurologic research as a Columbia undergraduate, doing summer work at the Columbia Neurological Institute in the laboratory of prominent mitochondrial expert Salvatore DiMauro, MD, now the Lucy G. Moses Professor of Neurology there.

Upon finishing his neurology residency, Dr. Mehler decided to take another unusual step: not to pursue a fellowship or mentorship. “I just don't do well that way. I do well discovering things for myself.”

Instead, he applied to the NIH for what was then called a “teacher–investigator” award — today, the grants are called mentored career development awards (K series). “So when I finished my residency, I became a faculty member at Einstein immediately and started doing research,” he said.

Dr. Mehler said that his approach to research is almost entirely inductive. “The majority of people in the world who are smart are very logical, deductive thinkers, and some are a combination of deductive and inductive, but only a few people are purely inductive. That's me. I can take a complicated problem with multiple seemingly disparate moving parts and I can effortlessly find some unique novel commonality about them, but if you ask me to do a logical problem, that I have to work at. For me to put together innovative new answers to biomedical problems is a pleasure, but to think logically through a single problem that everyone else has thought about is a real challenge.”

THE ‘AHA’ INSIGHT

Dr. Mehler's laboratory focuses largely on the study of neurodegenerative diseases. A little over a decade ago, he hit on a novel theory: that disorders like Alzheimer disease and Huntington disease might not be diseases of aging, but actually represent fundamental disorders of development. This “aha!” insight was reported in Crain's New York Business last August, labeling Dr. Mehler as one of a dozen “Brainiacs” — New York scientists “unlocking the brain's power.”

Then about five years ago, Dr. Mehler decided that in order to advance his research — and his department's work — he needed to understand epigenetics. “I felt that I needed to discover and incorporate this rapidly evolving discipline into my work, but I had no experience in it,” he said. “Most people would take a sabbatical to discover the topic with an expert, but there was no one person who could teach me all that I needed to know to make a difference scientifically: the breadth of epigenetics as a field.”

So instead of a sabbatical, Dr. Mehler plunged himself into the whole field of epigenetics, and RNA epigenetics in particular. There, he became aware of a “second genome” that he said has been hiding in plain sight for decades, concealed by the accepted dictum that DNA codes for RNA and RNA codes for proteins, and proteins determine biological function — and everything else has either been labeled as “junk DNA” or functionally irrelevant.

“Our understanding of the human genome is particularly incomplete in terms of the nervous system, which is undergoing accelerated evolutionary innovations in the mammalian lineage compared to other organ systems,” he said.

“Ninety eight plus percent of the human genome is made of non–protein coding DNA sequences, and as you ascend the evolutionary tree, the proportion of non-protein coding DNA is directly correlated with organismic complexity. We will eventually identify probably several million biologically relevant non-protein-coding RNAs representing a large number of functional subclasses, and each has a spectrum of biological function considerably more sophisticated than those of proteins.”

It turns out, said Dr. Mehler, that the biological substrate that mediates gene-environment interactions is the epigenome — and these interactions are uniquely important for the integrity and optimal functioning of brain throughout the entire lifecycle. “Every cell of your body has an epigenome that is totally unique and different from every other cell, and is changing continuously.”

What that means for neuroscience is the focus of his lecture at the AAN annual meeting. For video highlights from the lecture, see the next issue of Neurology Today.